Gene therapy provides a viable treatment alternative for an array of diseases and disorders. Due to the well-known toxicity and immunogenicity of viral vectors, the development of synthetic delivery systems is gaining attention. Unfortunately, very little attention has been paid to the pharmacokinetics and development of predictive models. The overall goal of this proposal is to develop an understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of liposome mediated delivery of plasmid DNA, and to utilize this information to develop physiologically-based pharmacokinetic (PBPK) models. Initially, normal healthy mice will be used to optimize a liposome delivery vehicle and develop and validate a PBPK model. The incorporation of a ligand to the liposome:DNA complex should increase transfection of the gene and minimize delivery and expression in untargeted cells/tissues. This will be tested both in vitro and in vivo. Since synthetic DNA has shown to target expression in endothelial cells, we intend to incorporate a VEGF receptor ligand in hopes to further enhance delivery to vascular endothelial cells, and later incorporate a gene to prohibit angiogenesis. Tumor xenograft models will be used to investigate the PK and PD of vascular endothelium targeted gene therapeutics, and validated PBPK models will be developed.